Abstract
ObjectiveIn idiopathic inflammatory myopathies (IIM) infiltration of immune cells into muscle and upregulation of MHC-I expression implies increased antigen presentation and involvement of the proteasome system. To decipher the role of immunoproteasomes in myositis, we investigated individual cell types and muscle tissues and focused on possible immune triggers.MethodsExpression of constitutive (PSMB5, -6, -7) and corresponding immunoproteasomal subunits (PSMB8, -9, -10) was analyzed by real-time RT-PCR in muscle biopsies and sorted peripheral blood cells of patients with IIM, non-inflammatory myopathies (NIM) and healthy donors (HD). Protein analysis in muscle biopsies was performed by western blot. Affymetrix HG-U133 platform derived transcriptome data from biopsies of different muscle diseases and from immune cell types as well as monocyte stimulation experiments were used for validation, coregulation and coexpression analyses.ResultsReal-time RT-PCR revealed significantly increased expression of immunoproteasomal subunits (PSMB8/-9/-10) in DC, monocytes and CD8+ T-cells in IIM. In muscle biopsies, the immunosubunits were elevated in IIM compared to NIM and exceeded levels of matched blood samples. Proteins of PSMB8 and -9 were found only in IIM but not NIM muscle biopsies. Reanalysis of 78 myositis and 20 healthy muscle transcriptomes confirmed these results and revealed involvement of the antigen processing and presentation pathway. Comparison with reference profiles of sorted immune cells and healthy muscle confirmed upregulation of PSMB8 and -9 in myositis biopsies beyond infiltration related changes. This upregulation correlated highest with STAT1, IRF1 and IFNγ expression. Elevation of T-cell specific transcripts in active IIM muscles was accompanied by increased expression of DC and monocyte marker genes and thus reflects the cell type specific involvement observed in peripheral blood.ConclusionsImmunoproteasomes seem to indicate IIM activity and suggest that dominant involvement of antigen processing and presentation may qualify these diseases exemplarily for the evolving therapeutic concepts of immunoproteasome specific inhibition.
Highlights
Idiopathic inflammatory myopathies (IIM) are a heterogenous group of muscle diseases characterized by inflammatory infiltrates in the skeletal muscle
Based on the existing but so far indirect assumption of an involvement of the proteasome system in the pathogenesis of idiopathic inflammatory myopathies (IIM), we investigated the expression of all catalytic proteasome subunits in inflammatory and non-inflammatory myopathies in order to search for an activation of the 20S core complex in patients with autoimmune myositis
dendritic cells (DCs) were the leading subset with differences in all immunoproteasomal subunits followed by monocytes, CD8+
Summary
Idiopathic inflammatory myopathies (IIM) are a heterogenous group of muscle diseases characterized by inflammatory infiltrates in the skeletal muscle. Three major diseases are defined: dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). The main autoimmune response in DM resembles a microangiopathy affecting skin and muscle tissue. In polymyositis and inclusion body myositis, cytotoxic CD8+ T cells invade muscle fibers. All of the invaded fibers and numerous non-invaded fibers express increased amounts of major histocompatibility complex class I (MHC-I) molecules [1]. The presence of MHC-I/CD8+ complex is considered as a characteristic immunopathological marker of PM and IBM [2]. Continuous upregulation of expression of MHC class I molecules in muscle fibers is thought to induce an endoplasmic reticulum stress response with accumulation of misfolded glycoproteins and activation of nuclear factor kappa B (NF-kB). MHC-I/CD8+ complexes may form and perpetuate an autoinflammatory response [3]
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